Hitherto, ergotamine and ergometrine which are ergot-alkaloids have been used as pharmaceutical agents for treatment of migrain and as an uterine contracting agent, respectively. Also, various semi-synthesized alkaloids have been used clinically, and typical examples of such alkaloids include methylergometrine (as uterine contracting agent), dihydroergotamine (as agents for treatment of orthostatic hypotensive asthenia and migrain), dihydroergotoxine (as agent for improving brain and peripheral circulation disorders and as anti-hypertensive agent), bromocryptin (as agent for treatment of acromegalia, pituitary giantism and Parkinson's disease).
These ergot-alkaloids and compounds related thereto possess various pharmacological activities, and have been known to have hypotensive, vasodilating, anti-ulcer, gastric secretion inhibitory, brain metabolism improving activity, anti-depressive activities as well as dopamine-like activity as described in, for example, The Alkaloids, Vol. 15, Academic Press, 1975, pp1-40 and literature references cited therein; Life Science, 27, 349 (1980); Br. J. Pharmacol., 75, 143p (1982); Arzneim.-Forsch., 29, 1227 (1979); ibid., 29, 1213 (1979); German Offen., No. 2,617,738; J. Med. Chem., 21, 754 (1978); Life Science, 29, 2227 (1981); J. Pharm. Pharmacol., 28, 563 (1976); J. Med. Chem., 17, 300 (1974); ibid, 18, 892 (1975); ibid, 20, 1473 (1977); Experientia., 35, 1677 (1979); Br. Med. J., 4, 442 (1974), etc.
Further, extensive studies have been conducted on alkaloids for the purpose of developing pharmaceutical agents having excellent pharmacological activities as described in, for example, Collect. Czech. Chem. Commun., 39, 1768 (1974), ibid, 42, 1407 (1977), ibid, 47, 1757 (1982); J. Pharm. Sci., 70, 1319 (1981); Experientia, 28, 819 (1972); Yakuri to Chiryo (Pharmacology and Treatment), 12, 402 (1984); Arzneim.-Forsch., 33, 1094 (1983), ibid, 33, 1098 (1983); Swiss Pat. Nos. 551,975 and 551,976 (1976); Czech. Pat. No. 171,570 (1978); German Offen., Nos. 2,802,023 and 2,810,774 (1978), 2,935,685 and 2,935,684 (1980), 3,026,271 (1981), 3,240,727 (1983); European Patent Application No. 1,115 (1979), 8,802 (1980), 56,358 (1982); Fr. Demmande Nos. 2,421,176 (1979), 2,434,814 (1980), 2,479,829 (1981); U.S. Pat. Nos. 4,199,579 (1980), 4,321,381 (1982); Belgian Pat. Nos. 870,414 (1979), 896,609 (1983); Spanish Pat. No. 508,102 (1982); Japanese Patent Application (OPI) Nos. 53-84996, 54-115400, 55-89282, 56-156279, 57-156485, 58-194884, 58-85886, 59-176285, etc. (The term "OPI" as used herein refers to an unexamined published Japanese patent application.)
On the other hand, the compounds having an ergolin-8-ylmethyl group bonded to a 5-membered heterocyclic group have been reported in a small number of prior art references, e.g., Japanese Patent Application (OPI) Nos. 58-194884 59-206382 and 60-84286. Further, there is only a very limited number of publications, e.g., Japanese Patent Application (OPI) No. 59-206382 and 60-84286, with respect to the compounds wherein an ergolin-8-ylmethyl group is directly bonded to the nitrogen atom of a 5-membered heterocyclic group containing at least one nitrogen atom, which are closely related to the compounds of this invention.
Although these prior art compounds have excellent pharmacological activities, they are still unsatisfactory because of their weak activity, low selectivity of effects, and/or high toxicity.
As a result of extensive studies on ergot-alkaloid related compounds, the present inventors found that ergoline derivatives of the formula (I) of the present invention and the pharmaceutically acceptable acid addition salts thereof have excellent pharmacological activities.